Relationships between blood-brain barrier breakdown, Alzheimer's disease pathology, and memory in aging

项目摘要 阿尔茨海默病(AD)的主要病因理论是蛋白质β-淀粉样蛋白的沉积，然而它是 尚不清楚衰老如何影响淀粉样蛋白的积累，也不清楚为什么在淀粉样蛋白缺失的情况下会出现认知能力下降。证据 提示神经血管功能障碍，如血脑屏障(BBB)的破坏，与 神经退行性变和认知障碍，这种关系可能独立于淀粉样蛋白发生。 然而，血脑屏障破坏与AD生物标志物以及认知之间的直接关系尚未得到证实 在人类身上进行了彻底的研究。本研究的目的是使用一种新的多模式成像设计来检查 人类的血脑屏障如何分解与AD生物标志物萎缩、淀粉样蛋白和tau以及认知有关。BBB 将使用动态对比增强磁共振成像(DCE-MRI)在体内对击穿进行量化， 这使得可以检测到人脑中微妙的血脑屏障渗漏。Tau和Aβ都将以 体内分别使用正电子发射断层扫描(PET)示踪剂[18F]Flortaucipir和[11C]PIB。 神经退行性变将通过结构磁共振和情景记忆复合体进行测量 神经心理测试分数。目标1将确定血脑屏障的分解是否随着年龄的增长而增加，以及是否存在特定的 在正常老化过程中更容易受到伤害的区域。目标2将检查血脑屏障是否在颞叶崩溃 与更大的全球Aβ和区域Tau有关。此外，还将确定血脑屏障故障是否与 有更大的回溯性纵向Aβ和tau积累。最后，目标3将确定血脑屏障是否发生故障 与较小的颞叶体积和较差的记忆性能有关。两性关系 独立于淀粉样蛋白的血脑屏障受损与记忆能力回溯性纵向变化之间的关系 和Tau，也将被检查。这项研究的发现将有助于揭示AD的基本机制 在人脑中的发病机制，这对早期发现和开发新的 AD的治疗策略。建议的研究项目将实现申请者的培训目标，即 包括(1)发展多模式成像技能，(2)高级统计和数据分析培训，(3)培训 在AD的临床损害和病理生理学方面，(4)教学和指导技能的发展，(5) 提高有效的科学沟通能力；(6)职业发展。加州大学伯克利分校的海伦·威尔斯 神经科学研究所是尖端研究人员和世界级成像设备网络的所在地。这个 该项目的发起人William Jagust博士在将多模式神经成像方法应用于 研究衰老和老年痴呆症的问题。在过去，他还成功地指导了许多学生，这些学生 成为该领域的领导者。联合发起人苏珊娜·贝克博士是神经成像优化方面的专家 PET和MRI的量化，以及药代动力学建模。拟议的研究和 培训计划将为申请者提供获得有竞争力的博士后奖学金和 成功研究衰老和阿尔茨海默病。

Project Summary The major theory of causation for Alzheimer’s disease (AD) is deposition of the protein β-amyloid, however it is unclear how aging influences amyloid accumulation or why cognitive decline can occur in its absence. Evidence suggests that neurovascular dysfunction, such as the breakdown of the blood-brain barrier (BBB), is related to neurodegeneration and cognitive impairment, and that this relationship may occur independently of amyloid. However, the direct relationship between BBB breakdown and AD biomarkers, as well as cognition, has not been thoroughly investigated in humans. The aim of this study is to use a novel multi-modal imaging design to examine how BBB breakdown in humans is related to AD biomarkers of atrophy, amyloid and tau, and cognition. BBB breakdown will be quantified in vivo using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which allows for the detection of subtle BBB leakage in the human brain. Both tau and Aβ will be measured in vivo using the positron emission tomography (PET) tracers [18F] Flortaucipir and [11C] PiB, respectively. Neurodegeneration will be measured with structural MRI and episodic memory with a composite neuropsychological test score. Aim 1 will determine if BBB breakdown increases with age and if there are specific regions that are more vulnerable during normal aging. Aim 2 will examine if BBB breakdown in the temporal lobe is related to greater global Aβ and regional tau. In addition, it will be determined if BBB breakdown is associated with greater retrospective longitudinal Aβ and tau accumulation. Finally, Aim 3 will determine if BBB breakdown in the temporal lobe is related to smaller temporal lobe volumes and worse memory performance. Relationships between BBB breakdown and retrospective longitudinal change in memory performance, independent of amyloid and tau, will also be examined. The findings from this study will help unravel fundamental mechanisms of AD pathogenesis in the human brain, which has vital implications for early detection and the development of new treatment strategies for AD. The proposed research project will achieve the applicant’s training goals, which include (1) developing skills in multimodal imaging, (2) advanced statistics and data analysis training, (3) training in clinical impairment and pathophysiology of AD, (4) development of teaching and mentoring skills, (5) improvement of effective scientific communication skills, and (6) career development. UC Berkeley’s Helen Wills Neuroscience Institute is home to a network of cutting-edge researchers and world-class imaging facilities. The sponsor of the project, Dr. William Jagust, is at the forefront in applying multimodal neuroimaging methods to study questions of aging and AD. He also has successfully mentored numerous students in the past, who have become leaders in the field. The co-sponsor, Dr. Suzanne Baker, is an expert in optimization of neuroimaging quantification for both PET and MRI, as well as pharmacokinetic modeling. Both the proposed research and the training plan will provide the applicant with the skillset to secure a competitive post-doctoral fellowship and a successful research career studying aging and AD.